Hydrogel Compositions and Methods of Preparation Thereof

ABSTRACT

Block copolymers include hydrophobic and hydrophilic blocks having repeating units derived from ring opening polymerization of one or more cyclic carbonate monomers. The carbonate monomers are independently selected from compounds of formula (II): 
     
       
         
         
             
             
         
       
     
     wherein each Q′ and Q a  group independently represents a hydrogen, an alkyl group, a halide, a carboxy group, an ester group, an amide group, an aryl group, an alkoxy group, or a foregoing Q′ or Q a  group substituted with a carboxy group or an ester group, at least one Q′ and Q a  group includes an ester group; each Y independently represents O, S, NH, or NQ″; n is an integer from 0 to 6, wherein when n is 0, carbons labeled 4 and 6 are linked together by a single bond; each Q″ group independently represents an alkyl group, an aryl group, or a foregoing Q″ group substituted with a carboxy group, or an ester group.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of and claims priority toU.S. application Ser. No. 12/549,667, filed on Aug. 28, 2009,incorporated herein by reference in its entirety.

BACKGROUND

The present invention relates to hydrogel compositions and methods ofpreparation thereof.

Injectable polymeric hydrogels have been explored as an artificialextracellular matrix (ECM) for drug delivery and tissueremodeling/healing. These materials are attractive because of theircolloidal properties in water.

Three general strategies exist for preparing injectable hydrogels. Thefirst is based on physical interactions between polymer chains; thesecond strategy relies on an in situ synthesis, usually based on Michaeladdition chemistry; and the third strategy is based on thermoresponsivepolymers. The thermoresponsive hydrogel materials are used in a varietyof biotechnology applications. Thermoresponsive polymers spontaneouslyand reversibly undergo temperature induced viscosity change (e.g.,gelation) in water. Designing thermoresponsive polymers, however,represents a significant and ongoing challenge.

Poly(N-isopropylacrylamide), PNIPAM, is a typical example of athermoresponsive polymer, which shows a temperature-induced collapsefrom an extended coil to a globular structure in water upon heatingabove 32° C., referred to as the lower critical solution temperature forPNIPAM. Polymers that display this type of physicochemical response tothermal stimuli have been widely explored as potential injectabledrug-delivery systems. However, PNIPAM is not readily biodegradable andhas recently been shown to exhibit cytotoxicity.

Lutz, J. F; Hoth, A. Macromolecules 2006, 39, 893-896; and Lutz, J. F.;Akdemir O.; Hoth, A. J. Am. Chem. Soc. 2006, 40, 13046-13047 reportedanother class of thermoresponsive polymers derived from copolymers of2-(2-methoxyethoxy)ethyl methacrylate (MEO2MA) andoligo(ethyleneglycol)methacrylates (OEGMA). Copolymers of MEO₂MA andOEGMA exhibit lower critical solution temperatures that can be tunedbetween 26° C. to 90° C. simply by increasing the amount of OEGMA from 0to 100 mole %. Significantly, the thermosensitivity of these acrylatecopolymers was insensitive to concentration or ionic strength. Whiledetailed cytotoxicity studies have not been carried out, the well knownbiocompatibility of polyethylene glycol (PEG) oligomers and PEG polymerssuggests that copolymers of MEO₂MA and OEGMA are likely to be morebiocompatible than PNIPAM, although not readily biodegradable.

Another class of thermoresponsive polymers are derived using CLICKchemistry to tag hydrophobic and hydrophilic functional groups ontocyclic esters. Polymerization generates random graft copolymers having aunique balance of hydrophobic and hydrophilic functional groups. Thepolymers exhibit lower critical solution temperature (LCST) behavior inwater at elevated temperatures.

Recent advances in synthetic polymer chemistry have enabled thedevelopment of new and powerful strategies for the controlled synthesisof complex polymer architectures, block copolymers and functionalmaterials. Organic catalysts for the ring-opening polymerization (ROP)of heterocyclic monomers, and a number of catalyst classes have beensuccessfully used in ROP syntheses, including DMAP, phosphines,N-heterocyclic carbenes, bifunctional thiourea-amines, and superbasicamines. The polymers derived by ROP methods include aliphatic polyestersand polycarbonates which are useful for a number of purposes includingbulk packaging, resorbable medical implants, and drug delivery.

An ongoing need exists to extend synthetic advancements toward thedesign and preparation of new thermoresponsive polymers for injectabledelivery systems.

SUMMARY

The shortcomings of the prior art are overcome and additional advantagesare provided through the provision of biodegradable, biocompatiblethermoresponsive polymers derived from cyclic carbonate monomers. In oneembodiment, a block copolymer comprises a hydrophobic block and ahydrophilic block, wherein the hydrophobic block and the hydrophilicblock comprise repeating units derived from ring opening polymerizationof one or more cyclic carbonate monomers, wherein the one or more cycliccarbonate monomers are independently selected from compounds of thegeneral formula (II):

wherein each Q′ and Q^(a) group independently represents a hydrogen, analkyl group comprising 1 to 20 carbons, a halide, a carboxy group, anester group comprising one or more carbons, an amide group comprisingone or more carbons, an aryl group comprising 6 to 20 carbons, an alkoxygroup comprising one or more carbons, or a foregoing Q′ or Q^(a) groupsubstituted with a carboxy group or an ester group comprising one ormore carbons, at least one Q′ and Q^(a) group comprises an ester groupcomprising one or more carbons; each Y independently represents O, S,NH, or NQ″; n is an integer from 0 to 6, wherein when n is 0, carbonslabeled 4 and 6 are linked together by a single bond; each Q″ groupindependently represents an alkyl group comprising 1 to 20 carbons, anaryl group comprising 6 to 20 carbons, or a foregoing Q″ groupsubstituted with a carboxy group, or an ester group comprising one ormore carbons.

In another embodiment, a method of preparing a block copolymer, bysequentially forming a hydrophilic block and a hydrophobic block of theblock copolymer, wherein the hydrophilic block and the hydrophobic blockeach comprise repeating units derived by ring opening polymerization ofthe one or more cyclic carbonate monomers as described above inreference to formula (II).

In another embodiment, a hydrogel composition comprise an aqueousmixture of micelles comprising a block copolymer and a sequesteredagent, wherein the block copolymer comprises a hydrophobic block and ahydrophilic block, the hydrophobic block and the hydrophilic block eachcomprising repeating units derived from ring opening polymerization ofthe one or more cyclic carbonate monomers as described above inreference to formula (II).

In another embodiment, a method comprises treating an aqueous mixture ofa block copolymer with an agent to form a self-assembled nanostructurecontaining the block copolymer and the agent, wherein the blockcopolymer comprises a hydrophobic block and a hydrophilic block, thehydrophobic block and the hydrophilic block each comprising repeatingunits derived from ring opening polymerization of the one or more cycliccarbonate monomers as in reference to formula (II).

Additional features and advantages will become apparent from thefollowing drawings and detailed description.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The subject matter which is regarded as the invention is particularlypointed out and distinctly claimed in the claims at the conclusion ofthe specification. The foregoing and other objects, features, andadvantages of the invention are apparent from the following detaileddescription taken in conjunction with the accompanying drawings inwhich:

FIG. 1 is a ¹H-NMR (CDCl₃) spectrum of MTC-PEG₃₅₀.

FIG. 2 is graph of a GPC curve of TRC(PEG350)_(10, 30, 30) in THF.

FIG. 3 is a ¹H-NMR (CDCl₃) spectrum of TRC(PEG350)_(10, 30, 30).

FIG. 4 is a graph of the luminous transmittance measurement at 500 nmfor TRC(PEG350)_(10, 30, 30) in water (1 mg/1 mL) as a function oftemperature.

The detailed description explains the preferred embodiments of theinvention, together with advantages and features, by way of example withreference to the drawings.

DETAILED DESCRIPTION

Amphiphilic thermoresponsive hydrogels and methods of preparation aredisclosed herein. The amphiphilic thermoresponsive hydrogels comprise abiocompatible and biodegradable block copolymer prepared byorganocatalytic ring opening polymerization of cyclic carbonatemonomers. In water, the hydrogels are soft, nanostructured particlescomprising a hydrophobic core, which is capable of reversiblysequestering a biologically active agent (e.g., a drug), and ahydrophilic shell to control lower critical solution temperature (LCST)behavior. The hydrogels have a LCST of about 25° C. to about 50° C.,more specifically about 30° C. to about 40° C., at or near human bodytemperature of 37° C. (98.6° F.). The hydrogels are attractive for drugdelivery systems, smart surfaces, bioseparations, controlled filtration,and for controlling enzyme activity. Also disclosed are injectablecompositions comprising an aqueous mixture of loaded hydrogel and areversibly sequestered biologically active agent. The injectablecompositions are designed to undergo a rapid, reversible, sol-geltransition when heated through the LCST at or near body temperature. Thegelled particles remain in the vicinity of the injection site togradually release the sequestered biologically active agent.

Generally, the cyclic carbonate monomers are formed from precursorcompounds comprising three or more carbons, two or more X groups, andoptionally one or more carboxy groups (i.e., —COOH). The two or more Xgroups independently represent an alcohol, a primary amine, a secondaryamine, or a thiol group. All of the cyclic carbonate monomers used inpreparing the hydrogels are derived from precursor compounds having thegeneral formula (I):

wherein each X independently represents OH, NHR″, NH₂, or SH; n is aninteger from 0 to 6, wherein when n is 0, carbons labeled 1 and 3(attached to the X groups) are linked together by a single bond; each R′and R^(a) group independently represents a hydrogen, a halide, a carboxygroup, an alkyl group comprising 1 to 20 carbons, an ester groupcomprising 1 to 20 carbons, an amide group comprising 1 to 20 carbons,an aryl group comprising 3 to 20 carbons, an alkoxy group comprising 1to 20 carbons, or a foregoing R′ or R^(a) group substituted with acarboxy group; each R″ group independently represents an alkyl groupcomprising 1 to 20 carbons, an aryl group comprising 3 to 20 carbons, ora foregoing R″ group substituted with a carboxy group. The R′, R^(a) andR″ groups can also independently comprise a cycloaliphatic ring, anaromatic ring, and/or a heteroatom such as oxygen, sulfur or nitrogen.The R′, R^(a) or R″ groups can also together form a ring that caninclude a heteroatom such as oxygen, sulfur or nitrogen. In anembodiment, at least one of the R′, R^(a) or R″ groups independentlycomprises a carboxy group, or a protected carboxy group such as anester, amide or thioester. In another embodiment, n is 0 or 1, one R^(a)group is methyl or ethyl, and the other R^(a) group is a carboxy group.

“Aryl groups” as the term is used herein, include aromatic hydrocarbonssuch as benzene and naphthalene, and aromatic heterocycles includingoxazole, imidazole, thiazole, isoxazole, furan, pyrazole, isothiazole,pyridine, pyrazine, pyrimidine, pyridazine, and the like. An aryl groupcan comprise as few as three carbons.

Cyclic carbonate monomers derived from the precursors of formula (1)have the general formula (II):

wherein each Q′ or Q^(a) group independently represents a hydrogen, analkyl group of 1 to 20 carbons, a halide, a carboxy group, an acidchloride group, an ester group comprising one or more carbons, an amidegroup comprising one or more carbons, an aryl group comprising 3 to 20carbons, an alkoxy group comprising one or more carbons, or a foregoingQ′ or Q^(a) group substituted with a carboxy group, an acid chloridegroup, an ester group comprising one or more carbons; at least one Q′ orQ^(a) group comprises a reactive carboxyl group selected from the groupconsisting of carboxylic acid, acid chloride and ester groups comprisingone or more carbons; each Y independently represents O, S, NH or NQ″; nis an integer from 0 to 6, wherein when n is 0, carbons labeled 4 and 6(attached to each Y group) are linked together by a single bond; each Q″group independently represents an alkyl group comprising 1 to 20carbons, an aryl group comprising 3 to 20 carbons, or a foregoing Q″group substituted with a carboxy group, an acid chloride group, or anester group comprising one or more carbons. The Q′, Q^(a) and Q″ groupscan further independently comprise a cycloaliphatic ring, an aromaticring, and/or a heteroatom such as oxygen, sulfur or nitrogen. The Q′,Q^(a) or Q″ groups can also together form a ring that can include aheteroatom such as oxygen, sulfur or nitrogen. In an embodiment, n is 1,one Q^(a) group is a methyl or ethyl group, the other Q^(a) group is acarboxylic acid, acid chloride or ester group comprising one or morecarbons, and all Q′ and Q″ groups are hydrogen.

More specific precursor compounds have the general formula (III):

wherein each X′ independently represents OH, NHT″, NH₂, or SH; each T′can independently represent a hydrogen, a halide, a carboxy group (i.e.,the moiety —COOH), an alkyl group comprising 1 to 20 carbons, an estergroup comprising 1 to 20 carbons, an amide group, an aryl groupcomprising 3 to 20 carbons, an alkoxy group comprising 1 to 20 carbons,or a foregoing T′ group substituted with a carboxy group; each T″independently represents an alkyl group comprising 1 to 20 carbons, anaryl group comprising 3 to 20 carbons, or a foregoing T″ groupsubstituted with a carboxy group. The T′ and T″ groups can alsoindependently comprise a cycloaliphatic ring, an aromatic ring, or aheteroatom such as oxygen, sulfur or nitrogen. The T′ or T″ groups canalso together form a ring that can include a heteroatom such as oxygen,sulfur or nitrogen. In an embodiment, none of the T′ or T″ groupscomprises a carboxy group. In another embodiment, the T′ attached to thecarbon labeled 2 in formula (5) is an ethyl or methyl group, and allother T′ groups are hydrogen.

The cyclic carbonate monomers can comprise a cyclic carbonate, cycliccarbamate, cyclic urea, cyclic thiocarbonate, cyclic thiocarbamate,cyclic dithiocarbonate, or combinations thereof, derived from the two ormore X groups of formula (I), or X′ groups of formula (III). As shownabove the cyclic carbonate monomer can comprise a carboxylic acid, whichcan be converted to an ester comprising more than one carbon. It isunderstood that numerous synthetic pathways exist for forming estersfrom carboxylic acids and primary or secondary alcohols. Other numerousmethods exist for preparing active esters that can be displaced by aprimary or secondary alcohol to form an ester. The ester can be formedbefore, after, or simultaneously with the formation of the cycliccarbonyl group. It is also understood that one method of forming anester might be more suitable than another due to steric constraints ofthe alcohol, relative hazards associated with the reagents, and otherconsiderations effecting reaction efficiency, yield, and/orenvironmental impact.

More specific cyclic carbonate monomers, derived from the precursorcompounds of general formula (III), have the general formula (IV):

wherein each Y′ independently represents O, S, NH or NU″; M′ representsOH, chloride, or an ester comprising one or more carbons; each U′ groupindependently represents a hydrogen, a halide, an alkyl group comprising1 to 20 carbons, a carboxy group (i.e., —COOH), an ester comprising oneor more carbons, an amide group comprising one or more carbons, athioester group comprising one or more carbons, or an aryl groupcomprising 3 to 20 carbons. Each U″ group independently represents analkyl group comprising 1 to 20 carbons or an aryl group comprising 3 to20 carbons, or a foregoing U″ group substituted with an ester group orcarboxy group. In an embodiment, none of the U′ or U″ groups comprise anester group or a carboxy group. In another embodiment, Y′ is oxygen, theU′ group attached to the carbon labeled 5 is a methyl or ethyl group, M′represents OH, chloride, or an ester comprising one or more carbons, andall other U′ groups are hydrogen.

The above-described cyclic carbonate monomers, such as those possessinga carboxy group or active ester group, can be derivatized to form othercyclic carbonate monomers effective in forming hydrogels. For example,the carboxylic acid group of formulas (II) or (IV) can be converted toan active carbonyl either in situ (such as with DCC) or stepwise (e.g.,by way of an acid chloride, p-nitrophenyl ester, or other active ester).The active carbonyl can then be converted into an ester, amide orthioester group by reaction with an alcohol, amine or thiol group,respectively to produce cyclic carbonyl compounds of varyinghydrophobicity or hydrophilicity.

More specific cyclic carbonate monomers contain an ester group and havethe formula (V):

wherein each Z′ independently represents O, S, NH or NV″; R represents agroup having one or more carbons, each V′ group independently representsa hydrogen, a halide, an alkyl group comprising 1 to 20 carbons, anester group comprising one or more carbons, an amide group comprisingone or more carbons, an aryl group comprising 3 to 20 carbons, or analkoxy group comprising one or more carbons; each V″ group independentlyrepresents an alkyl group comprising 1 to 20 carbons or an aryl groupcomprising 3 to 20 carbons, or a foregoing V″ group substituted with anester group comprising one or more carbons. In an embodiment, each Z′ isoxygen, the V′ at carbon labeled 5 is a methyl or ethyl group, and allother V′ groups are hydrogen.

Even more specific cyclic carbonate monomers comprise cyclic carbonateshaving the formula (VI):

wherein R comprises one or more carbons. Particularly useful R groupsinclude alkyl groups comprising from 1 to 20 carbons (e.g., ethyl andlauryl), and poly(alkylene ether)s having the structure (VII):

wherein n is an integer from 1 to 25, more particularly 3-15; n′ is aninteger from 1 to 10; and R^(c) is hydrogen or an alkyl group having 1to 20 carbons. In an embodiment, the poly(alkylene ether) is apoly(ethylene glycol) monoalkyl ether having a molecular weight of fromabout 200 to about 100,000 Daltons. In another embodiment, n′ is 1, n isan integer from 1 to 25, and R^(c) is methyl.

A non-limiting example of a precursor compound useful in forming manycyclic carbonate monomers of formula (6) is 2,2-bis(methylol)propionicacid, bis-MPA, a building block for biocompatible dendrimers. The cycliccarbonate monomers derived from bis-MPA are used to introducefunctionality and connectivity into a ROP polyester or polycarbonateblock copolymer in a controlled fashion, thereby tailoring thehydrophilic/hydrophobic balance for a desired LCST response. One methodof introducing this functionality into bis-MPA is shown in Scheme I:

As shown, bis-MPA is first converted to a benzyl ester (i), followed byreaction with triphosgene (ii) to form the benzyl ester,2-benzyloxycarbonyl-2-methyltrimethylene carbonate (MTC-OBn). MTC-OBn isthen debenzylated (iii) to produce the free carboxylic acid,2-hydroxycarbonyl-2-methyltrimethylene carbonate (MTC-OH). MTC-OH canthen be esterified with an alcohol (ROH) to form an ester (MTC-OR),where R is a group comprising one or more carbons. ROH is a monomeric orpolymeric alcohol comprising a pendant or terminal alcohol group. Twopathways are shown for forming the ester MTC-OR. In the first pathway,(iv), the free acid, MTC-OH, is treated in situ with a suitable carboxyactivating agent, such as dicyclohexylcarbodiimide, DCC, and an alcohol,ROH, to form the MTC-OR in a single step. Alternatively, MTC-OH can beconverted first (v) to an acid chloride,2-chlorocarbonyl-2-methyltrimethylene carbonate (MTC-C1) followed bytreatment (vi) of MTC-C1 with ROH in the presence of a base to formMTC-OR. Both pathways are exemplary and are not meant to be limiting.The following conditions are typical for the reactions shown in Scheme1: (i) Benzylbromide (BnBr), KOH, DMF, 100° C., 15 hours, 62% yield ofthe benzyl ester of bis-MPA. (ii) triphosgene, pyridine, CH₂Cl₂, −78° C.to 0° C., 95% yield of MTC-OBn. (iii) Pd/C (10%), H₂ (3 atm), EtOAc,room temperature, 24 hours, 99% yield of MTC-OH. (iv) ROH, DCC, THF,room temperature, 1 to 24 hours. (v) (COCl)₂, THF, room temperature, 1hour, 99% yield of MTC-C1. (vi) ROH, NEt₃, room temperature, 3 hoursyields MTC-OR. As used herein, room temperature is generally defined asabout 15° C. to about 30° C.

Isomerically pure precursor compounds that have a hydrogen attached toan asymmetric carbon adjacent to an ester group or carboxy group can beconverted to cyclic carbonate monomers without undergoing significantracemization of the asymmetric carbon. An enantiomeric excess of 80% ormore, more specifically of 90%, is possible. In an embodiment, thecyclic carbonate monomer comprises an asymmetric carbon as an (R)isomer, in an enantiomeric excess of greater than 80%, more specificallygreater than 90%. In another embodiment, the cyclic carbonate monomercomprises an asymmetric carbon as an (S) isomer, in an enantiomericexcess greater than 80%, more specifically greater than 90%.

Examples of cyclic carbonate monomers useful in forming hydrogelsinclude but are not limited to:

wherein n^(a) is an integer from 1 to 25, n^(b) is an integer from 1 to25, more particularly 3 to 15, and R^(C) is a alkyl group comprising 1to 20 carbons. In formula (IX), when n^(a) is 9, the monomer isdodecanoxycarbonyl-2-methyltrimethylene carbonate, (MTC-C12, whereinC#=number of carbons). In formula (X), when n^(b) is about 10, andR^(C)=methyl, the monomer is 2-poly(ethyleneglycol)oxycarbonyl-2-methyltrimethylene carbonate (MTC-PEG₅₅₀).

MTC-PEG_(m) is derived from MTC-OH, or an active ester derivativethereof, and a poly(ethylene glycol) monolalkyl ether. The PEG subscriptm (e.g., “550” in “PEG₅₅₀”) represents the number average molecularweight (M_(n)) of the poly(ethylene glycol) monoalkyl ether. Thepoly(ethylene glycol) monoalkyl ether can have an M_(n) from about 100to about 50,000, more particularly about 100 to about 5,000 and mostparticularly from about 100 to about 1000.

The cyclic carbonate monomers are independently selected from theabove-described cyclic carbonate monomers to form the hydrogel blockcopolymer. Isotactic forms of the polymers can be produced depending onthe cyclic monomer(s), its isomeric purity, and the polymerizationconditions.

The hydrogels are prepared by sequentially polymerizing by ring openingmethods one or more different cyclic carbonate monomers to form thehydrophilic block and the hydrophobic block of the block copolymer. Theblock copolymer can comprise more than one hydrophobic block and/orhydrophilic block if desired. The blocks are distinguished by theiraffiliation for water as well as their chemical structure. Thus, n″sequential ROP steps are used to form an n″-block copolymer, where n″ isan integer greater than or equal to 2, more specifically 2 to 10, andeven more specifically 2 to 4. Many configurations of block sequencesare possible. For example, diblock copolymers comprising A and B blockscan be represented as -AB-copolymers. Triblock copolymers comprising Aand B blocks can be represented as -ABA- or -BAB-copolymers. Tetrablockcopolymers comprising A and B blocks can be represented as-ABAB-copolymers. Triblock polymers comprising A, B, and C blocks can berepresented, for example, as -ABC-, -ACB-, or -BAC-copolymers.Tetrablock copolymers comprising A, B and C blocks can be represented,for example, as -ABCA-, -ABCB, -ACAB, -BCAB-, -BCAC-, -CABA, and-CABC-copolymers. The above examples of block sequences in blockcopolymers are not meant to be limiting. Due to the large number ofpossible hydrophilic and hydrophobic cyclic carbonate monomers, andpossible block configurations, the block copolymers can be tailored to aspecific lower critical solution temperature behavior and/or bindingstrength to a biologically active agent.

The hydrophobic block of the block copolymer has an average degree ofpolymerization (DP) of more than 0 and less than or equal to about 40,more particularly about 10 to about 30. The hydrophilic block has anaverage degree of polymerization of about 5 to about 90, moreparticularly 20 to 60.

More specifically, the method of forming a hydrogel comprises forming afirst mixture comprising one or more cyclic carbonate monomers, acatalyst, an initiator, and an optional solvent. The first mixture isthen heated and agitated to effect polymerization of the one or morecyclic carbonate monomers, forming a second mixture comprising a firstpolymer, the A block. One or more additional cyclic carbonate monomers,and an optional second portion of catalyst are added to the secondmixture to form a third mixture. The third mixture is then agitated toeffect polymerization of the B block. At a concentration of 0.1 to 10g/L in water, the resulting block copolymer, a hydrogel, has areversible LCST of from about 25° C. to about 50° C. The LCST can bedetermined by a sudden change in physico-chemical property of an aqueousmixture of the block copolymer. For example, the LCST is determined tobe a temperature at which the transmittance of an aqueous solution ofthe block copolymer (e.g., a concentration of 1 mg/mL) is largelydecreased (e.g., 10-20%), compared to that of the aqueous mixture underLCST (e.g., at 10° C.). Alternatively, the LCST transition can bedetermined by differential scanning calorimetry (DCS) or dynamicmechanical analysis. The LCST can be determined from the onset of anendothermic peak or sudden increase in modulus.

An exemplary homopolymer prepared from a cyclic carbonate monomer offormula (II) has the general formula (XI):

wherein at least one W′ or W^(a) group comprises an ester, m is aninteger greater than 1, “Initiator” is a polymerization initiator moiety(e.g., C₆H₅CH₂O derived from benzyl alcohol; the initiator can also be apolymer chain having a terminal or pendant hydroxyl, amine, or thiolgroup). Each Z independently represents O, S, NH or NW″; n is an integerfrom 0 to 6, wherein when n is 0, carbons labeled 4 and 6 are linkedtogether by a single bond; and each W′ and W^(a) group independentlyrepresents a hydrogen, a halide, an alkyl group comprising 1 to 20carbons, an ester group comprising 1 to 20 carbons, an amide groupcomprising 1 to 20 carbons, an aryl group comprising 3 to 20 carbons, analkoxy group comprising 1 to 20 carbons, or a foregoing W′ or W^(a)group substituted with an ester; each W″ group independently representsan alkyl group comprising 1 to 20 carbons, an aryl group comprising 3 to20 carbons, or a foregoing W″ group substituted with an ester. Moreparticularly, m is an integer from 1 to 10,000, from 100 to 5000, orfrom 100 to 1000. In an embodiment, n is 1, Z is oxygen, one W^(a) groupis a methyl or ethyl group, another W^(a) group is a —CO₂R group whereinR is an alkyl ester comprising 1 to 20 carbons, and all other W′ groupsare hydrogen.

The polymer of formula (VII) is a living polymer, meaning the terminalZ—H group can initiate the polymerization of a new chain (i.e., block),comprising the same or a different cyclic carbonate monomer. Typically,additional catalyst is added to drive the polymerization of the newblock.

An exemplary living polymer prepared from a cyclic carbonate monomer offormula (V) has the general formula (XII):

wherein “Initiator” is as defined above, each Z′ independentlyrepresents O, S, NH or NV″; R represents a group comprising one or morecarbons, each V′ group independently represents a hydrogen, a halide, analkyl group comprising 1 to 20 carbons, an ester group comprising one ormore carbons, an amide group comprising one or more carbons, an arylgroup comprising 3 to 20 carbons, or an alkoxy group comprising one ormore carbons; each V″ group independently represents an alkyl groupcomprising 1 to 20 carbons or an aryl group comprising 3 to 20 carbons,or a foregoing V″ group substituted with an ester group comprising oneor more carbons. In an embodiment, Z′ is oxygen, V′ attached to carbonlabeled 5 is methyl or ethyl, all other V′ groups are hydrogen, and R isa group comprising one or more carbons.

A non-limiting example of a diblock copolymer derived from threedifferent cyclic carbonate monomers, formed by two sequentialpolymerizations is illustrated in Scheme 2:

In the first polymerization, benzyl alcohol initiates ROP of MTC-C2 inthe presence of a catalyst, producing the A block homopolymer,poly(2-ethoxycarbonyl-2-methyltrimethylene carbonate (PMTC-C2). Amixture comprising two monomers, MTC-C12 and MTC-PEG₃₅₀ (n is about 7-8in the structure of Scheme 2), and optional additional catalyst, is thenadded to PMTC-C2. PMTC-C2 initiates polymerization to form the B block,shown in brackets in Scheme 2, comprising a random copolymer of MTC-C12and MTC-PEG₅₅₀. The resulting block copolymer, labeled TRC_(a, b, c) isa thermoresponsive polycarbonate (TRC). The subscripts in the nameTRC_(a, b, c) represent the degree of polymerization (DP), of eachcyclic carbonate monomer in the block copolymer. Subscript a is aninteger from more than 0 to less than or equal to about 40, moreparticularly about 10 to about 30. The sum of subscripts b and ctogether can be from 5 to 90, more particularly 20 to 60. Thehydrophilic block can comprise MTC-PEG₅₅₀ and MTC-C12 in a mole ratio is0.5 to 6 respectively, more particularly a mole ratio of 1 to 3respectively. The number average molecular weight of the block copolymercan be from 600 to 60,000 g/mol, more particularly 15,000 and 40,000g/mol.

Each of the monomers in Scheme 2 is derived from the2,2-bis(methylol)propionic acid (bis-MPA). The A block is hydrophobicdue to the MTC-C2. The B block is hydrophilic due to the MTC-PEG_(m).The B block also contains hydrophobic subunits derived from MTC-C12. Byvarying the amounts of MTC-C12 and MTC-PEG_(m) in the B block, thehydrophilic properties of the B block can be tuned to a specific LCSTresponse. The hydrophobic/hydrophilic balance can further be adjusted byvarying the molecular weight of the PEG, the length of the ester alkylchain in MTC-C12, the length of the ester alkyl chain in the A block,and/or by adding additional hydrophilic and/or hydrophobic blocks to theblock copolymer.

The ring opening polymerization is generally conducted in a reactorunder inert atmosphere such as nitrogen or argon. The polymerization canbe performed by solution polymerization in an inactive solvent such asbenzene, toluene, xylene, cyclohexane, n-hexane, dioxane, chloroform anddichloroethane, or by bulk polymerization. The ROP reaction temperaturecan be from 20° to 250° C. Generally, the reaction mixture is heated atatmospheric pressure for 0.5 to 72 hours to effect polymerization.Subsequently, additional cyclic monomer and catalyst can be added to thesecond mixture to effect block polymerization if desired.

Exemplary ROP catalysts include tin(II)-2-ethyyhexanoate (stannousoctoate), tin (II) butoxide, tin (IV) alkoxides, tetramethoxy zirconium,tetra-iso-propoxy zirconium, tetra-iso-butoxy zirconium, tetra-n-butoxyzirconium, tetra-t-butoxy zirconium, triethoxy aluminum, tri-n-propoxyaluminum, tri-iso-propoxy aluminum, tri-n-butoxy aluminum,tri-iso-butoxy aluminum, tri-sec-butoxy aluminum,mono-sec-butoxy-di-iso-propoxy aluminum, ethyl acetoacetate aluminumdiisopropylate, aluminum tris(ethyl acetoacetate), tetraethoxy titanium,tetra-iso-propoxy titanium, tetra-n-propoxy titanium, tetra-n-butoxytitanium, tetra-sec-butoxy titanium, tetra-t-butoxy titanium,tri-iso-propoxy gallium, tri-iso-propoxy antimony, tri-iso-butoxyantimony, trimethoxy boron, triethoxy boron, tri-iso-propoxy boron,tri-n-propoxy boron, tri-iso-butoxy boron, tri-n-butoxy boron,tri-sec-butoxy boron, tri-t-butoxy boron, tri-iso-propoxy gallium,tetramethoxy germanium, tetraethoxy germanium, tetra-iso-propoxygermanium, tetra-n-propoxy germanium, tetra-iso-butoxy germanium,tetra-n-butoxy germanium, tetra-sec-butoxy germanium and tetra-t-butoxygermanium; halogenated compound such as antimony pentachloride, zincchloride, lithium bromide, tin(IV) chloride, cadmium chloride and borontrifluoride diethyl ether; alkyl aluminum such as trimethyl aluminum,triethyl aluminum, diethyl aluminum chloride, ethyl aluminum dichlorideand tri-iso-butyl aluminum; alkyl zinc such as dimethyl zinc, diethylzinc and diisopropyl zinc; tertiary amines such as triallylamine,triethylamine, tri-n-octylamine and benzyldimethylamine; heteropolyacidssuch as phosphotungstic acid, phosphomolybdic acid, silicotungstic acidand alkali metal salt thereof; zirconium compounds such as zirconiumacid chloride, zirconium octanoate, zirconium stearate and zirconiumnitrate. More particularly, the catalyst is zirconium octanoate,tetraalkoxy zirconium or a trialkoxy aluminum compound.

Other ROP catalysts include metal-free organocatalysts that can alsoprovide a platform to polymers having controlled, predictable molecularweights and narrow polydispersities. Examples of organocatalysts for theROP of cyclic esters, carbonates and siloxanes are4-dimethylaminopyridine, phosphines, N-heterocyclic carbenes (NHC),bifunctional aminothioureas, phosphazenes, amidines, and guanidines.

The ROP reaction mixture comprises at least one catalyst and, whenappropriate, several catalysts together. The ROP catalyst is added in aproportion of 1/20 to 1/40,000 moles relative to the cyclic monomers,and preferably of 1/100 to 1/20,000 moles. In an embodiment, thecatalyst is a combination of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),and 1-(3,5-bis(trifluoromethyl)phenyl-3-cyclohexyl-2-thiourea, TU.

The ROP reaction mixture also comprises an initiator. Initiatorsgenerally include nucleophiles such as alcohols, amines or thiols. Theinitiator can be mono functional, difunctional or multifunctional suchas dendritic, polymeric or related architectures. Monofunctionalinitiators can include nucleophiles with protected functional groupsthat include thiols, amines, acids and alcohols. A typical initiator isphenol or benzyl alcohol.

Well-known apparatuses can be used for performing the ROPpolymerization. An example of a tower type reaction apparatus includes areaction vessel comprising helical ribbon wings and transformationalspiral baffles. Examples of sideways type reaction apparatuses includesideways type one-or twin-shaft kneaders comprising agitation shaftsthat have a row of transformational wings arranged in parallel to eachother. In addition, the reaction apparatus can be either a batch type ora continuous one.

The hydrogels comprise block copolymers having a number-averagemolecular weight of about 1,000 to about 100,000, more particularlyabout 10,000 to about 40,000. The hydrophilic block typically has anumber average molecular weight of 1,500 to 6,000. The hydrophobic blocktypically has a has a number average molecular weight of 8,000 to35,000.

The unloaded hydrogel particles (without a sequestered biologicallyactive agent) have an average spherical diameter of 20 to 1000nanometers, more specifically 20 to 200 nanometers, and even morespecifically 20 to 100 nanometers.

The hydrogels can self-assemble into micelles in aqueous solution, andtherefore have utility as transport vehicles for biologically activeagents, particularly in the form of injectable compositions. Aninjectable hydrogel composition comprises an aqueous mixture of micelles(self-assembled nanostructures) containing the hydrogel and asequestered biologically active agent. These loaded micelles are freelymoving below the LCST (i.e., mutually repulsed resulting in lowviscosity). Above the LCST, the micelles rapidly, reversibly, coalesceto form a gel. The gel provides an in situ medium for the slow releaseof the biologically active agent to the surrounding tissue of theinjected site.

A method of forming an injectable composition comprises treating anaqueous mixture of a biodegradable block copolymer with a biologicallyactive agent to form micelles containing the block copolymer and thebiologically active agent, wherein the block copolymer comprises ahydrophobic block and a hydrophilic block, the hydrophobic block and thehydrophilic block each comprising repeating units derived from ringopening polymerization of one or more cyclic carbonate monomers.

The term “biologically active agent” as used herein means any substancewhich can affect any physical or biochemical properties of a biologicalorganism. Biological organisms include but are not limited to viruses,bacteria, fungi, plants, animals, and humans. In particular, abiologically active agent includes any substance intended for thediagnosis, cure, mitigation, treatment, or prevention of disease inhumans or other animals, or to otherwise enhance physical or mental wellbeing of humans or animals. Examples of biologically active agentsinclude, but are not limited to, organic and inorganic compounds,proteins, peptides, lipids, polysaccharides, nucleotides, DNAs, RNAs,other polymers, and derivatives thereof. Examples of biologically activeagents include antibiotics, fungicides, anti-viral agents,anti-inflammatory agents, anti-tumor agents, cardiovascular agents,anti-anxiety agents, hormones, growth factors, steroidal agents, and thelike. Other examples include microorganisms such as bacteria and yeastcells, viral particles, plant or animal or human cells, and the like.

The hydrogels can also be applied to conventional molding methods suchas compression molding, extrusion molding, injection molding, hollowmolding and vacuum molding, and can be converted to molded articles suchas various parts, receptacles, materials, tools, films, sheets andfibers. A molding composition can be prepared comprising the polymer andvarious additives, including for example nucleating agents, pigments,dyes, heat-resisting agents, antioxidants, weather-resisting agents,lubricants, antistatic agents, stabilizers, fillers, strengthenedmaterials, fire retardants, plasticizers, and other polymers. Generally,the molding compositions comprise 30 wt. % to 100 wt. % or more of thepolymer based on total weight of the molding composition. Moreparticularly, the molding composition comprises 50 wt. % to 100 wt. % ofthe polymer. The polymers, and articles molded therefrom, can bebiodegradable.

The polymer product of the ROP polymerization can be formed intofree-standing or supported films by known methods. Non-limiting methodsto form supported films include dip coating, spin coating, spraycoating, and doctor blading. Generally, such coating compositionscomprise 0.01 wt. % to 90 wt. % of the polymer based on total weight ofthe coating composition. More particularly, the molding compositioncomprises 1 wt. % to 50 wt. % of the polymer based on total weight ofthe coating composition. The coating compositions generally also includea suitable solvent necessary to dissolve the polymer product.

The coating compositions can further include other additives selected soas to optimize desirable properties, such as optical, mechanical, and/oraging properties of the films. Non-limiting examples of additivesinclude surfactants, ultraviolet light absorbing dyes, heat stabilizers,visible light absorbing dyes, quenchers, particulate fillers, and flameretardants. Combinations of additives can also be employed.

The following examples demonstrate the preparation of cyclic carbonatemonomers and the polymerization of the monomers to form homopolymers andblock copolymers.

EXAMPLES Example 1 Synthesis of MTC-C2

2,2-bis(methylol)propionic acid (bis-MPA) (22.1 g, 0.165 mol) was addedin ethanol (150 mL) with Amberlyst-15 (6.8 g) and refluxed overnight.The resins were then filtered out and the filtrate was evaporated.Methylene chloride (200 mL) was added to the resulting viscous liquid tofilter the unreacted reagent and by-products. The solution was driedover Mg50₄, filtered, and the solvent was removed in vacuo. Ethyl2,2-bis(methylol)propionate was obtained as a clear and colorless liquid(21.1 g, 86% yield).

A solution of triphosgene (19.5 g, 0.065 mol) in CH₂Cl₂ (200 mL) wasthen added stepwise to a CH₂Cl₂ solution (150 mL) of ethyl2,2-bis(methylol)propionate (21.1 g, 0.131 mol) and pyridine (64 mL,0.786 mol) over 30 min at −75° C. with dry-ice/acetone. The reactionmixture was kept stirring for another 2 hours under chilled conditions,then allowed to warm to room temperature. Saturated NH₄Cl aqueoussolution (200 mL) was added to the reaction mixture to decompose excesstriphosgene. The organic phase was then treated with 1N aqueous HCl (200mL), followed by saturated NaHCO₃ (200 mL), brine (200 mL), and water(200 mL). After the CH₂Cl₂ solution was dried over MgSO₄ and evaporated,the residue was recrystallized from ethyl acetate to give white crystals(13.8 g, 56% yield). ¹H NMR (400 MHz in CDCl₃): d 4.68 (d, 2H, CH₂OCOO),4.25 (q, 1H, OCH₂CH₃), 4.19 (d, 2H, CH₂OCOO), 1.32 (s, 3H, CH₃), 1.29(t, 3H, CH₃CH₂O). ¹³C NMR (100 MHz in CDCl₃): d 171.0, 147.5, 72.9,62.1, 39.9, 17.3, 13.8. HR-ESI-MS: m/z calculated for C₈H₁₂O₅+Na211.0582; found 221.0578.

Example 2 Synthesis of MTC-PEG₅₅₀

Methoxy poly(ethylene glycol) (MPEG₅₅₀) (M_(n)=550 g/mol, 8.0 g, 0.015mol) and MTC-OH (2.8 g, 0.017 mol) were dissolved in THF (100 mL).N,N′-Dicyclohexylcarbodiimide (DCC) (3.5 g, 0.017 mol) was added to theflask. The formed DCC-urea derivative began to precipitate after about 5minutes. The solution was stirred overnight to complete the reaction,followed by filtration of the DCC-urea, and evaporation of THF. Thecrude product was dissolved in anhydrous diethyl ether (500 mL) andcooled in the refrigerator. Residual MTC-OH precipitated in cold diethylether and was removed by filtration. The resulting solution wasconcentrated, and the product was dried in a vacuum oven until constantweight. Yield: ˜80%. ¹H-NMR (400 MHz in CDCl₃): =4.73-4.70 (d, 2H,—CH₂OCOOCH₂CCH₃—), 4.38-4.36 (t, 2H, PEG-CH₂CH₂—OCO), 4.22-4.20 (d, 4H,—CH₂OCOOCH₂CCH₃—), 3.65 (m, 4H, OCH₂CH₂ PEG), 3.38 (s, 3H, OCH₂CH₂OCH₃PEG), 1.38 (s, 3H, CCH₃CH₂CCOOCH₂).

Example 3 Synthesis of MTC-PEG₃₅₀

Methoxy poly(ethylene glycol) (MPEG₃₅₀) (M_(n)=350 g/mol, 5.0 g, 0.014mol) and MTC-OH (3.0 g, 0.019 mol) were dissolved in THF (100 mL).N,N′-Dicyclohexylcarbodiimide (DCC) (3.8 g, 0.019 mol) was added to theflask. The DCC-urea derivative began to precipitate after about 5minutes. The solution was stirred overnight to complete the reaction,followed by filtration of the DCC-urea, and evaporation of THF. Thecrude product was dissolved in anhydrous diethyl ether (500 mL) andcooled in a refrigerator. Residual MTC-OH precipitated in cold diethylether and was removed by filtration. The resulting solution wasconcentrated, and the product was dried in a vacuum oven until constantweight. Yield: ˜80%. ¹H-NMR (400 MHz in CDCl₃): =4.73-4.70 (d, 2H,—CH₂OCOOCH₂CCH₃—), 4.38-4.36 (t, 2H, PEG-CH₂CH₂—OCO), 4.22-4.20 (d, 4H,—CH₂OCOOCH₂CCH₃—), 3.65 (m, 4H, OCH₂CH₂ PEG), 3.38 (s, 3H, OCH₂CH₂OCH₃PEG), 1.38 (s, 3H, CCH₃CH₂CCOOCH₂).

Example 4 Synthesis of MTC-PEG₁₂₀

Methoxy poly(ethylene glycol) (MPEG₁₂₀) (M_(n)=120 g/mol, 3.0 g, 0.025mol) and MTC-OH (5.2 g, 0.033 mol) were dissolved in THF (150 mL).N,N′-Dicyclohexylcarbodiimide (DCC) (6.7 g, 0.033 mol) was added to theflask. The DCC-urea derivative began to precipitate after about 5minutes. The solution was stirred overnight to complete the reaction,followed by filtration of the DCC-urea, and evaporation of THF. Thecrude product was dissolved in anhydrous diethyl ether (500 mL) andcooled in a refrigerator. Residual MTC-OH precipitated in cold diethylether and was removed by filtration. The resulting solution wasconcentrated, and the product was dried in a vacuum oven until constantweight. Yield: ˜80%. ¹H-NMR (FIG. 1, 400 MHz in CDCl₃): =4.73-4.70 (d,2H, —CH₂OCOOCH₂CCH₃—), 4.38-4.36 (t, 2H, PEG-CH₂CH₂—OCO), 4.22-4.20 (d,4H, —CH₂OCOOCH₂CCH₃—), 3.65 (m, 4H, OCH₂CH₂ PEG), 3.38 (s, 3H,OCH₂CH₂OCH₃ PEG), 1.38 (s, 3H, CCH₃CH₂CCOOCH₂).

Example 5 Synthesis of MTC-C12

A mixture of bis-MPA (30.4 g, 0.227 mol), potassium hydroxide (88%assay; 13.5 g, 0.241 mol), and a mixture of DMF (20 mL) and acetonitrile(180 mL) was heated to 100° C. for 1 hour. Lauryl bromide (60 mL, 0.250mol) was added to the warm solution, and stirring was continued at 100°C. for 16 hours. The reaction mixture was cooled to filter salts and thefiltrate was evaporated under vacuum. Ethyl acetate (200 mL) was addedto the residue. The organic solution was washed with water (200 mL×3),dried with Mg50₄, filtered, and concentrated to give lauryl2,2-bis(methylol)propionate as a clear oil that solidified upon standingfor several days (62.2 g, 91% yield).

Lauryl 2,2-bis(methylol)propionate (30.1 g, 0.100 mol) was thendissolved in CH₂Cl₂ (300 mL) and pyridine (50 mL, 0.6 mol) and thesolution was chilled to −78° C. under N₂. A solution of triphosgene(15.0 g, 0.05 mol) in CH₂Cl₂ was added dropwise over 1 hour, at whichpoint the reaction mixture was allowed to warm to room temperature for 2hours. The reaction was quenched by addition of saturated aqueous NH₄Cl(200 mL), after which the organic solution was washed with 1 M aqueousHCl (200 mL×3), saturated aqueous NaHCO₃ (200 mL), dried over MgSO₄,filtered and concentrated to give MTC-C12 as a white solid (28.1 g, 86%yield). MTC-C12 for polymerization was further purified byrecrystallization from ethyl acetate. ¹H NMR (400 MHz in CDCl₃): d 4.68(d, 2H, CH₂OCOO), 4.19 (d, 2H, CH₂OCOO), 4.18 (t, 1H, OCH₂CH₂), 1.65 (m,2H, OCH₂CH₂), 1.33 (s, 3H, CH₃), 1.32-1.21 (m, 18H, CH₂), 0.87 (t, 3H,CH₂CH₃). ¹³C NMR (100 MHz in CDCl₃): δ 171.1, 147.4, 72.9, 66.3, 40.1,31.8, 29.5, 29.4, 29.3, 29.2, 29.1, 28.3, 25.6, 22.6, 17.5, 14.0.

Example 5 Preparation of Thermoresponsive Polycarbonate,TRC(PEG₃₅₀)_(10, 30, 30) with Degree of Polymerizations (DPs) of 10, 30,30 for MTC-C2, MTC-PEG₅₅₀, and MTC-C12, Respectively

Thermoresponsive polycarbonate (TRC_(a, b, c)) block copolymers withdegree of polymerizations (DPs) of a, b, c for MTC-C2, MTC-PEG₃₅₀, andMTC-C12, respectively, were prepared from a series of two ring openingpolymerizations (ROP): (i) ROP of MTC-C2, and then (ii) ROP of a mixtureof MTC-PEG₅₅₀ and MTC-C12. First, benzyl alcohol (10 mg, 93 μmol) andsparteine (22 mg, 94 μmol) were dissolved in CH₂Cl₂ (0.5 mL). MTC-C2(0.17 g, 0.90 mmol) and thiourea catalyst (35 mg, 95 μmol) were added tothe solution, and the mixture was polymerized at room temperature for 1day in a glove box. At the end of the first polymerization monitored byNMR spectroscopy, MTC-PEG₃₅₀ (1.97 g, 2.8 mmol), and MTC-C12 (0.91 g,2.8 mmol), and additional TU/sparteine (2.5˜5.0 mol %) catalystsdissolved in CH₂Cl₂ (1.5 mL) were added. The polymerization proceeded atroom temperature for 2 days in a glove box. At the end of reaction, anexcess of benzoic acid was added to deactivate the catalyst, and theCH₂Cl₂ was removed by evaporation. The product polymer was purified bydialysis (MWCO=1,000) in CH₃OH for 1 day and then dried under vacuum togive yellowish viscous liquid. Yield: ˜50%, M_(n) (NMR)=35,100 g/mol,PDI (GPC in THF, FIG. 2)=1.15. ¹H-NMR (400 MHz in CDCl₃, FIG. 3):=7.45-7.30 (m, Ph initiator), 5.08 (s, Ph-CH₂ initiator), 4.30-4.15 (br,OCOOCH₂ polymer of MTC-Et, MTC-PEG, MTC-C12), 4.10 (q, OCH₂CH₃ polymerof MTC-Et), 4.06-4.02 (t, OCH₂CH₂(CH₂)₉CH₃ polymer of MTC-C12),Et-CH₂OCOOCH₂CCH₃—), 4.38-4.36 (t, 2H, PEG-CH₂CH₂—OCO), 4.22-4.20 (d,4H, —CH₂OCOOCH₂CCH₃—), 3.65 (m, 4H, OCH₂CH₂ polymer of MTC-PEG), 3.38(s, 3H, OCH₂CH₂OCH₃ polymer of MTC-PEG), 1.55 (br, 2H, OCH₂CH₂(CH₂)₉CH₃polymer of MTC-C12 and 3H, OCH₂CH₃ polymer of MTC-Et), 1.40-1.20 (br,18H, OCH₂CH₂(CH₂)₉CH₃ polymer of MTC-C12 and OCOOCH₂CCH₃CH₂ polymer ofMTC-Et, MTC-PEG, MTC-C12), 0.82-0.79 (t, 3H, OCH₂CH₂(CH₂)₉CH₃ polymer ofMTC-C12). FIG. 4 is a graph showing the luminous transmittance at 500 nmfor TRC (PEG=350)_(10, 30, 30) in water (1 mg/1 mL) as a function oftemperature. The luminous transmittance begins falling at about 25° C.,steeply falling from 35° C. to 45° C., thus evidencing the LCSTtransition for this material. The temperature was step-wise increased byevery 1-2° C.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising,” when used in this specification, specify thepresence of stated features, integers, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneore more other features, integers, steps, operations, elementcomponents, and/or groups thereof.

The corresponding structures, materials, acts, and equivalents of allmeans or step plus function elements in the claims below are intended toinclude any structure, material, or act for performing the function incombination with other claimed elements as specifically claimed. Thedescription of the present invention has been presented for purposes ofillustration and description, but is not intended to be exhaustive orlimited to the invention in the form disclosed. Many modifications andvariations will be apparent to those of ordinary skill in the artwithout departing from the scope and spirit of the invention.

The foregoing description of the embodiments of this invention has beenpresented for purposes of illustration and description. It is notintended to be exhaustive or to limit the invention to the precise formdisclosed, and many modifications and variations are possible. Suchmodifications and variations that may be apparent to a person skilled inthe art are intended to be included within the scope of this inventionas defined by the accompanying claims.

1. A method of preparing a block copolymer, by sequentially forming ahydrophilic block and a hydrophobic block of the block copolymer,wherein the hydrophilic block and the hydrophobic block each compriserepeating units derived by ring opening polymerization of one or morecyclic carbonate monomers, wherein the one or more cyclic carbonatemonomers are independently selected from compounds of the generalformula (II):

wherein each Q′ and Q^(a) group independently represents a hydrogen, analkyl group comprising 1 to 20 carbons, a halide, a carboxy group, anester group comprising one or more carbons, an amide group comprisingone or more carbons, an aryl group comprising 6 to 20 carbons, an alkoxygroup comprising one or more carbons, or a foregoing Q′ or Q^(a) groupsubstituted with a carboxy group or an ester group comprising one ormore carbons, at least one Q′ and Q^(a) group comprises an ester groupcomprising one or more carbons; each Y independently represents O, S,NH, or NQ″; n is an integer from 0 to 6, wherein when n is 0, carbonslabeled 4 and 6 are linked together by a single bond; each Q″ groupindependently represents an alkyl group comprising 1 to 20 carbons, anaryl group comprising 6 to 20 carbons, or a foregoing Q″ groupsubstituted with a carboxy group, or an ester group comprising one ormore carbons.
 2. The method of claim 1, wherein the ring openingpolymerization is catalyzed by an organic catalyst.
 3. A methodcomprising treating an aqueous mixture of a block copolymer with anagent to form a self-assembled nanostructure containing the blockcopolymer and the agent, wherein the block copolymer comprises ahydrophobic block and a hydrophilic block, the hydrophobic block and thehydrophilic block each comprising repeating units derived from ringopening polymerization of one or more cyclic carbonate monomers, whereinthe one or more cyclic carbonate monomers are independently selectedfrom compounds of the general formula (II):

wherein each Q′ and Q^(a) group independently represents a hydrogen, analkyl group comprising 1 to 20 carbons, a halide, a carboxy group, anester group comprising one or more carbons, an amide group comprisingone or more carbons, an aryl group comprising 6 to 20 carbons, an alkoxygroup comprising one or more carbons, or a foregoing Q′ or Q^(a) groupsubstituted with a carboxy group or an ester group comprising one ormore carbons, at least one Q′ and Q^(a) group comprises an ester groupcomprising one or more carbons; each Y independently represents O, S,NH, or NQ″; n is an integer from 0 to 6, wherein when n is 0, carbonslabeled 4 and 6 are linked together by a single bond; each Q″ groupindependently represents an alkyl group comprising 1 to 20 carbons, anaryl group comprising 6 to 20 carbons, or a foregoing Q″ groupsubstituted with a carboxy group, or an ester group comprising one ormore carbons.